6qav
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of ULK2 in complexed with MRT68921== | |
| + | <StructureSection load='6qav' size='340' side='right' caption='[[6qav]], [[Resolution|resolution]] 2.05Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6qav]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QAV OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QAV FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=HVH:~{N}-[3-[[5-cyclopropyl-2-[(2-methyl-3,4-dihydro-1~{H}-isoquinolin-6-yl)amino]pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide'>HVH</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6qav FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qav OCA], [http://pdbe.org/6qav PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qav RCSB], [http://www.ebi.ac.uk/pdbsum/6qav PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qav ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/ULK2_HUMAN ULK2_HUMAN]] Serine/threonine-protein kinase involved in autophagy in response to starvation. Acts upstream of phosphatidylinositol 3-kinase PIK3C3 to regulate the formation of autophagophores, the precursors of autophagosomes. Part of regulatory feedback loops in autophagy: acts both as a downstream effector and a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) via interaction with RPTOR. Activated via phosphorylation by AMPK, also acts as a negative regulator of AMPK through phosphorylation of the AMPK subunits PRKAA1, PRKAB2 and PRKAG1. May phosphorylate ATG13/KIAA0652, FRS2, FRS3 and RPTOR; however such data need additional evidences. Not involved in ammonia-induced autophagy or in autophagic response of cerebellar granule neurons (CGN) to low potassium concentration. Plays a role early in neuronal differentiation and is required for granule cell axon formation: may govern axon formation via Ras-like GTPase signaling and through regulation of the Rab5-mediated endocytic pathways within developing axons.<ref>PMID:18936157</ref> <ref>PMID:21460634</ref> <ref>PMID:21460635</ref> <ref>PMID:21690395</ref> <ref>PMID:21795849</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Autophagy is essential for cellular homeostasis and when deregulated this survival mechanism has been associated with disease development. Inhibition of autophagy initiation by inhibiting the kinase ULK1 has been proposed as a potential cancer therapy. While inhibitors and crystal structures of ULK1 have been reported, little is known about the other closely related kinase ULK2. Here we present the crystal structure of ULK2 in complex with ATP competitive inhibitors. Surprisingly, the ULK2 structure revealed a dimeric assembly reminiscent of dimeric arrangements of auto-activating kinases suggesting a role for this association in ULK activation. Screening of a kinase focused library of pre-clinical and clinical compounds revealed several potent ULK1/2 inhibitors and good correlation of inhibitor binding behavior with both ULK kinases. Aurora A was identified as a major off-target of currently used ULK1 inhibitors. Autophagic flux assays demonstrated that this off-target activity by strongly inducing autophagy in different cellular systems conferred an additional layer of complexity in the interpretation of cellular data. The data presented here provides structural models and chemical starting points for the development of ULK1/2 dual inhibitors with improved selectivity for future exploitation of autophagy inhibition. | ||
| - | + | Conservation of structure, function and inhibitor binding in UNC-51-like kinase 1 and 2 (ULK1/2).,Chaikuad A, Koschade SE, Stolz A, Zivkovic K, Pohl C, Shaid S, Ren H, Lambert LJ, Cosford NDP, Brandts CH, Knapp S Biochem J. 2019 Feb 19. pii: BCJ20190038. doi: 10.1042/BCJ20190038. PMID:30782972<ref>PMID:30782972</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 6qav" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Non-specific serine/threonine protein kinase]] | ||
| + | [[Category: Arrowsmith, C H]] | ||
| + | [[Category: Bountra, C]] | ||
[[Category: Chaikuad, A]] | [[Category: Chaikuad, A]] | ||
| - | [[Category: | + | [[Category: Structural genomic]] |
| - | [[Category: | + | [[Category: Edwards, A M]] |
[[Category: Knapp, S]] | [[Category: Knapp, S]] | ||
| - | [[Category: | + | [[Category: Autophagy]] |
| - | [[Category: | + | [[Category: Inhibitor complex]] |
| + | [[Category: Kinase]] | ||
| + | [[Category: Sgc]] | ||
| + | [[Category: Transferase]] | ||
| + | [[Category: Ulk2]] | ||
Revision as of 15:36, 27 February 2019
Crystal structure of ULK2 in complexed with MRT68921
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